In 2016, there were an estimated 5.9 million intravitreal injections (IVIs) performed in the United States, growing from just 1 million in 2009.¹ With the exponential increase in IVI procedures performed, more attention has turned to the syringes that are used to perform them.

Nearly all syringes that are used for intravitreal injection (IVI) are not approved by the US Food and Drug Administration for this purpose and therefore are used off label, with the exception of prefilled syringes loaded with FDA-approved medication. Standard IVI syringes, often used with intravitreal bevacizumab and vial-drawn medication, were originally designed for use in other areas of medicine, for example, syringes for insulin injections and tuberculin skin tests. Many of the syringes adapted for ophthalmic use have the features that make them ideal for IVI procedures; however, nearly all of them are also coated with silicone oil to reduce injection resistance during use. Although silicone oil is otherwise considered inert, droplets left in the eye following IVI are possibly implicated with concerning risks.

INTRAOCULAR SILICONE OIL DROPLETS

Retina specialists have been aware that deposits of silicone oil can be observed following IVIs, leading researchers to investigate more thoroughly. A cross-sectional, comparative study was done in 2019 examining the prevalence of silicone oil droplets in the vitreous of patients who had undergone IVI procedures compared to patients who had not. Using ultrasonography, silicone oil droplets were found in the eyes of 76% of patients who had received treatment and found in only 3% of patients that had not received any treatment.²

Silicone oil droplets may build up over time, especially in those patients who have received many injections in the past. The presence of these intravitreal droplets following injections may cause patients to experience floaters in their vision. Floaters have been shown to negatively impact patient quality of life and are perceived by many to be a significant health problem. Evidence of the impact that these side effects have on patient wellbeing was put on display in the 2018 ASRS PAT Survey, which found that among ophthalmologists in the United States who had performed bevacizumab (Avastin; Genentech) IVIs that year, 1.8% had at least 1 patient seek legal action because of intraocular silicone oil. The survey also found that 5.2% of ophthalmologists that year performed at least 1 vitrectomy to treat symptomatic floaters produced by silicone oil.³ These potentially preventable vitrectomies come with risks, such as retinal detachment, vitreous hemorrhage, and endophthalmitis, all of which can result in loss of vision.

Beyond directly interfering with patients’ vision, silicone oil droplets have also been speculated to contribute to acute inflammatory reactions after intravitreal injection of anti-VEGF agents. While the mechanism of these interactions is not completely understood, evidence suggests this may occur as a result from silicone oil-protein interactions. Previous studies have shown silicone oil-protein interactions can cause changes in protein conformation or create aggregates with immunogenic potential.⁴ A recent case-control study conducted by this authorship group supports this hypothesis, correlating the presence of silicone oil release with increased anterior-chamber inflammation following intravitreal injection of aflibercept.⁵

Some manufacturers have taken steps to address the safety concerns regarding siliconized syringes. At the beginning of 2021, Becton-Dickinson (BD) released a safety notice acknowledging the risk of floaters due to silicone oil release and advised that “to reduce this risk of silicone floaters and inflammation or irritation that may occur, health care providers should only use the syringes and needles provided with ocular medications that are specifically designed and labelled for intravitreal injection.” They also stated that all their future shipments of syringes will contain a caution notice. The manufacturer of Braun syringes, which includes the Injekt-F, also released a similar notice in early 2021.

REVIEW OF SYRINGES IN OPHTHALMIC PRACTICE

As evidence regarding the link between silicone oil and ocular inflammation has grown, it has become more important to consider the on-label and off-label syringes commonly used in ophthalmic practice today. For intravitreal injections, a syringe that can precisely deliver a small volume (typically .02 mL to .1 mL) is required. Minimal or zero dead space in the syringe is also ideal to minimize the amount of medication wasted and the amount of air inside the syringe, which is linked to increased release of silicone oil.⁶ Luer-lock tips may be preferred by some because they allow physicians to securely attach their needle of choice. Fixed needles provide convenience and the ability for manufacturers to prefill syringes, and they generally have less dead space than syringes with detachable needles.⁷ Prefilled syringes have been thought to provide more precise medication measurement and to reduce wasted medication, and they have been shown to decrease preparation time per injection.⁸ Below are descriptions of some of the most commonly used syringes in ophthalmic practice; however, this is not intended for analyzing or listing every syringe available. FDA-cleared syringes were limited to syringes that have been developed specifically for ophthalmic use.

SYRINGES NOT DEVELOPED FOR OPHTHALMIC USE

• BD Luer-Lok is a commonly used syringe; it is siliconized, comes with a Luer lock tip that allows needles to be swapped out, and it can be distributed prefilled with aflibercept in the United States.
• BD Ultra-Fine is a popular, widely available syringe originally designed for insulin injections. It has a fixed needle that features minimal dead space. In a recent study, it was found to be highly correlated with silicone droplets left in the vitreous.⁶
• BD Plastipak is widely available and affordable. This syringe is siliconized, and it uses a Luer slip tip. This allows needles to easily be attached and detached; however, needles may be less secure than those with a Luer-lock tip because there is no locking mechanism.
• Braun Injekt-F is a silicone-free syringe, nearly eliminating the risk of residual droplets. It utilizes the Luer slip tip, which, like the Luer lock, results in a higher dead space than most syringes with fixed needles.

The amount of silicone oil released by various syringes in different conditions was tested in another study by one of the authors, Dr. Gustavo Melo. Among the syringes listed above, on average, the BD Ultra-Fine released the most silicone oil, followed by the BD Luer-Lok, then narrowly the BD Plastipak, and the Braun Injekt-F released the least amount (Table 1).

SYRINGES CLEARED BY FDA OR PENDING CLEARANCE

Currently, the only fillable syringe to be considered on label and that has been cleared by the FDA for intravitreal use is the Tribofilm Staclear syringe (Figure 2). Developed in collaboration with ophthalmologists, the syringe features a fixed needle, zero dead space design, and although is not silicone free, it has silicone fixed to the lumen of the syringe by a special crosslinking technique to prevent the formation of droplets while still reducing resistance. Because this technique immobilizes the silicone, it also prevents uneven lubrication that can sometimes increase frictional forces. They are also launching another Staclear syringe with a Luer slip tip, which is expected in late 2021.

The Zero Residual syringe (SJJ Solutions) is another syringe designed for ophthalmic use. It features a dedicated Luer lock cap that enables air-free prefilling and has negligible dead space. It is lubricated with a small amount of silicone. Another study analyzing silicone oil release from syringes included the Zero Residual syringe, and it found that when subjected to agitation, it released levels similar to the BD Luer-Lok. When the syringes were not subjected to agitation, the Zero Residual released the least amount of silicone oil, releasing less than half the amount of the next best performing syringe.⁶ Determination for FDA clearance is expected by the end of 2021.

The Zero Residual silicone free syringe (SJJ Solutions) is almost identical to the model above, with one important distinction being that it is silicone free. An FDA determination is also expected by the end of 2021.

FDA CLEARANCE FOR INTRAVITREAL INJECTIONS

For any syringe to become cleared by the FDA, it must comply with United States Pharmacopeia (USP) Chapter 789 testing for particulate matter in ophthalmic solutions. The testing involves analyzing the solution dispensed from syringes to ensure that all particles are below a mean threshold size and within specific size distribution. The testing ensures this by examining the product coming out of the syringe via a light scattering method and a light obscuration method. The USP Chapter 789 tests can be complemented by USP Chapter 1788 testing, which requires a more advanced sensor that has the highest sensitivity specification (0.5 μm) of any system used for USP particle testing.^9-13

CONCLUSIONS

Intravitreal injections have become the most common ophthalmic procedure performed each year. Although most injections are uncomplicated, floaters and intraocular inflammation are 2 of the most observed side effects and are associated with silicone oil droplets. The deposition of silicone oil during injections is potentially avoidable through the use of syringes that have been thoroughly tested and meet FDA specifications. As more syringes are specifically developed for intravitreal use and more care is taken in selection of syringes used in procedures, it may be possible to improve patient outcomes. RP

REFERENCES

1. Williams GA. IVT injections: health policy implications. Rev Opthalmol. 2014. https://www.reviewofophthalmology.com/article/ivt-injections-health-policy-implications
2. Melo GB, Dias Junior CS, Morais FB, et al. Prevalence of silicone oil droplets in eyes treated with intravitreal injection. Int J Retina Vitreous. 2019 Sep 11;5:34. doi: 10.1186/s40942-019-0184-9. PMID: 31528356; PMCID: PMC6737593.
3. American Society of Retina Specialists. Preferences and Trends (PAT) Survey. https://www.asrs.org/asrs-community/pat-survey
4. Anderson WJ, da Cruz NFS, Lima LH, Emerson GG, Rodrigues EB, Melo GB. Mechanisms of sterile inflammation after intravitreal injection of antiangiogenic drugs: a narrative review. Int J Retina Vitreous. 2021;7(1):37. Published 2021 May 7. doi:10.1186/s40942-021-00307-7
5. Melo GB, Figueira ACM, Batista FAH, et al. Inflammatory reaction after aflibercept intravitreal injections associated with silicone oil droplets released from syringes: a case-control study. Ophthalmic Surg Lasers Imaging Retina. 2019;50(5):288-294. doi:10.3928/23258160-20190503-05
6. Melo GB, Emerson GG, Dias CS Jr, et al. Release of silicone oil and the off-label use of syringes in ophthalmology. Br J Ophthalmol. 2020;104(2):291-296. doi:10.1136/bjophthalmol-2019-313823
7. Kesten JM, Ayres R, Neale J, et al. Acceptability of low dead space syringes and implications for their introduction: A qualitative study in the West of England. Int J Drug Policy. 2017;39:99-108. doi:10.1016/j.drugpo.2016.09.005
8. Sassalos TM, Paulus YM. Prefilled syringes for intravitreal drug delivery. Clin Ophthalmol. 2019;13:701-706. doi:10.2147/OPTH.S169044
9. United States Pharmacopeia <787> subvisible particulate matter in therapeutic protein injections.
10. United States Pharmacopeia <788> particulate matter in injections.
11. United States Pharmacopeia <789> particulate matter in ophthalmic solutions.
12. United States Pharmacopeia <729> globule size distribution in lipid injectable emulsions.
13. United States Pharmacopeia <1788> methods for the determination of particulate matter in injections and ophthalmic solutions.